Abstract The abuse use of electronic cigarette (e-cig) or vaping is a worldwide health problem. Major symptoms of e-cig, or vaping, product use-associated lung injury (EVALI) include cough and shortness of breath. In general, sensory irritation induced by chemical or mechanical stimulation in the lower airway, such as trachea triggers reflexive cough and dyspnea. However, we lack a direct assessment of sensory activation induced by e-cig constituents, tetrahydrocannabinol (THC) and vitamin E acetate that potentially cause EVALI. Furthermore, there is a lack of research data whether chronic vaping neurogenically hyper-sensitizes the airway. In our parent grant project, we electrophysiologically record event-related potentials (ERP) in the nasal mucosa to objectively assess sensory irritation evoked by e-cig flavorings, nicotine, PG/VG and flavored popular e-liquids. Our data have demonstrated dose-dependent sensory activation evoked by these e-liquid constituents. We hypothesize that certain e-liquid constituents cause sensory irritation in the trachea, which subsequently triggers reflexive cough and dyspnea, and that long-term e-cig vapor exposure hyper-sensitizes the airway mucosa. We will test our hypotheses by pursuing research: 1) measuring ERP from mouse tracheal mucosa to evaluate sensory irritation caused by e-liquid constituents, THC and vitamin E acetate, 2) monitor and correlate tracheal mucosal sensory irritation with respiratory alteration, and 3) determining whether 2-week vapor exposure sensitizes the tracheal mucosa resulting in potentiated responses to e-liquid constituents and tussive stimuli. We have accumulated sufficient data from our parent grant project that will enable us to speed up this proposed research substantially by narrowing the tested stimulus concentration ranges. Importantly, we have successfully measured in vivo ERP responses to some e-liquid flavorings, nicotine, and tussigenic capsaicin, and acetic acid from tracheal epithelium that has intact nerve innervation. This direct recording from trachea mucosa presents an innovative approach for the risk assessment of e-cig vaping. Together, our preliminary data promise for time-sensitive, significant results towards a better understanding of the health effects of e-cig vaping and causal factors of EVALI and help guide FDA regulation of e-cig manufacture and sale.